Multiple myeloma (MM) remains an incurable disease. Although most patients respond to initial treatment, drug resistance develops eventually. Circulating tumor cells in the blood of patients with MM (myeloma CTCs) hold the promise of representing a minimally invasive window into the genetics of MM, and have been implicated as a reservoir of drug-resistant disease as well as prognostic markers. However, little is known about the mutations these cells harbor. Obtaining genetic information from myeloma CTCs provides an opportunity to follow genetic evolution of MM in real time, to predict responses to treatment, and to identify genetic alterations that lead to drug resistance. The objective of this KO8 proposal is to investigate the nature of myeloma CTCs, to determine how they relate to primary MM cells in the bone marrow, and to identify how the genetic profile of myeloma CTCs evolves over time and in response to therapeutic drugs in MM patients. This approach will establish a framework for early detection of genetic resistance in the blood of MM patients and identify targets for therapeutic intervention. I am a medical hematologist/oncologist with a PhD and prior research experience in immunology who is seeking K08 support for mentored research in Dr. Todd Golub's laboratory. The K08 award will provide the protected time I need for advanced training prior to transitioning to an independent investigator position. Under Dr. Golub's mentorship I intend to learn modern tools for genomic analysis of cancers and experimental skills to establish genetic alterations as promising candidates for development of cancer therapeutics. I will be guided by my co-mentor Dr. Kenneth Anderson, in selecting appropriate alterations and therapeutics for translation into clinical trials. I will devote a minium of 80% of my time to a focused research program in myeloma genomics and will complement this with 20% of my effort dedicated to clinical care of patients with hematologic malignancies. DFCI and the Broad Institute of MIT and Harvard are internationally recognized research institutions with expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. The division of Medical Oncology at DFCI has a distinguished record of training physician-scientists. I have assembled an Advisory Committee of internationally recognized experts in the field of cancer genomics, single cell analysis, myeloma biology, and clinical research that will monitor my progress. I will also engage in training activities including seminar series, international meetings and formal coursework to acquire additional skills in translational investigation and computational genomic analysis. This research proposal is part of a structured plan with scientific, technical, clinical training and career development components. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator at an academic center.